New transgenic mouse models for studies of integrin function in fibroblastic cells

Cells interact with the extracellular matrix via cell surface receptors called integrins. During the 10 past years we have systematically worked on one particular integrin that we have identified and characterized, the alpha11beta1 integrin. In 2007 we pu blished a paper describing a tooth eruption phenotype of mice lacking integrin alpha11. Together with a Canadian group we also published a paper in 2007 describing for the first time a paracrine mechanism for stromal alpha11beta1 integrin-stimulated tumor igenesis. During the last few years as we have entered a new phase in our studies focused on testing the function of the integrin in different disease models, a whole new picture has revealed itself. It is thus becoming clear that integrin alpha11beta1 i s a unique fibroblast marker that is induced in myofibroblasts during wound healing, in the tumor stroma and in experimental fibrosis of the skin and cornea (tissues tested so far). Unpublished data from these studies have shown that mice lacking the alph a11 subunit on their fibroblasts develop markedly less fibrosis, display weaker wounds, and to a lesser degree support tumor growth. In the pending application we seek support to further examine the molecular mechanism of alpha11 action, focusing on two s pecific aspects: 1) transcriptional regulation of the alpha11 gene (including TGF-beta responsiveness, which is a major mechanism for myofibroblast differentiation) and, 2) the development of new transgenic mouse models, to support and validate our exist ing knockout models. We believe that a strong focus on molecular mechanisms will be most beneficial for a deeper understanding of the role of this integrin in physiological and pathophysiological processes.